title: Furanylazaindoles: potent anticancer agents in vitro and in vivo.
abstract: Preliminary biological data on 7-anilino-6-azaindoles (8-11) suggested that hydrophobic substituents at C7 contribute to enhancement of antiproliferative activity. A novel series of 7-aryl-6-azaindole-1-benzenesulfonamides (12-22) were developed and showed improved cytotoxicity compared to ABT751 (5). The conversion of C7 phenyl rings into C7 heterocycles led to a remarkable improvement of antiproliferative activity. Among all the synthetic products, 7-(2-furanyl)-1-(4-methoxybenzenesulfonyl)-6-azaindole (21) exhibited the most potent anticancer activity against KB, HT29, MKN45, and H460 cancer cell lines with IC50 values of 21.1, 32.0, 27.5, and 40.0 nM, respectively. Bioassays indicated that 21 not only inhibits tubulin polymerization by binding to tubulin at the colchicine binding site but also arrests the cell cycle at the G2/M phase with slight arrest at the sub-G1 phase. Compound 21 also functions as a vascular disrupting agent and dose-dependently inhibits tumor growth without significant change of body weight in an HT29 xenograft mouse model. Taken together, compound 21 has potential for further development as a novel class of anticancer agents.
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University , 250 Wuxing Street, Taipei, 11031, Taiwan, Republic of China.
authors.forename: Hsueh-Yun
authors.initials: HY
authors.lastname: Lee
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
authors.forename: Min-Chieh
authors.initials: MC
authors.lastname: Su
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Liu
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Kuo
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Chang
authors.forename: Jian-Sung
authors.initials: JS
authors.lastname: Wu
authors.forename: Chih-Ying
authors.initials: CY
authors.lastname: Nien
authors.forename: Samir
authors.initials: S
authors.lastname: Mehndiratta
authors.forename: Chi-Yen
authors.initials: CY
authors.lastname: Chang
authors.forename: Su-Ying
authors.initials: SY
authors.lastname: Wu
authors.forename: Mei-Jung
authors.initials: MJ
authors.lastname: Lai
authors.forename: Jang-Yang
authors.initials: JY
authors.lastname: Chang
authors.forename: Jing-Ping
authors.initials: JP
authors.lastname: Liou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D019073:HT29 Cells; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D058105:Polymerization / Q000187:drug effects; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C586841:7-(2-furanyl)-1-(4-methoxybenzenesulfonyl)-6-azaindole; C490492:ABT751; D000970:Antineoplastic Agents; D006574:Heterocyclic Compounds, 2-Ring; D007211:Indoles; D013449:Sulfonamides; D014404:Tubulin